Thyroid gland
The thyroid is one of the largest endocrine glands. It curves across the anterior surface of the trachea just inferior to the thyroid cartilage, which makes up most of the anterior larynx. The isthmus is the thin connection between the two sides of the gland. It controls the speed at which the body uses up energy, synthesises new proteins, and also has a hand in determining how sensitive the body is to other hormones. It does this by releasing T3 and T4, as well as calcitonin. Output is regulated by thyroid-stimulating hormone, which is secreted by the anterior pituitary gland, which is regulated itself by thyrotropin-releasing hormone, secreted by the hypothalamus. Gross anatomy The gland's size and weight tends to vary as hereditary, environmental, and nutritional factors all play a part, but it generally weighs about 34g. It is typically very red in colour due to it's extensive blood supply. It is butterfly-shaped, with two wing-like lobes, one on each side connected via the isthmus. Some people will also have a 'pyramidal lobe', a small superior projection of the isthmus. The thyroid gland lies just inferior to the thyroid cartilage and covers the anterior surface of the trachea, reaching posteriorly to the oesophagus and carotid sheath. Its superior ridge is at the oblique line on the thyroid cartilage, its inferior ridge is around the 5th/6th tracheal ring, although it moves substantially during swallowing due to its firm adhesion to the trachea. A thin fibrous sheath called the capsula glandulae thyroidea covers the whole gland with an internal and external layer. The external layer is continuous with the pretracheal fascia and carotid sheath. Infrahyoids cover it anteriorly, whilst the sternocleidomastoids cover it laterally. Posteriorly, it is fixed to the cricoid and tracheal cartilage, and the cricopharyngeus muscle Histology The thyroid contains thousands of hollow spheres lined by simple cuboidal epithelium called thyroid follicles. The follicle cells surround a core of a viscous colloid containing large quantities of soluble proteins. Each follicle is supplied by an extensive network of capillaries which deliver nutrients and regulatory hormones and remove waste and secretions. Colloid serves as a storage for iodide ions, which it absorbs from the bloodstream in order to be used in hormone synthesis. Around 25% of the body's iodine is in the thyroid follicle's colloid. Follicle cells synthesize a globular protein called thyroglobulin and secrete it into the follicle cavity (into the colloid). Thyroglobulin molecules contain tyrosine, an essential component of all thyroid hormones. C cells (or parafollicular cells), are a second group of endocrine cells that lie sandwiched between the cuboidal follicle cells and their basement membranes. They are larger than the follicular cells, and do not stain easily (hence 'C' cells - C for clear). C cells produce calcitonin, a hormone that helps to regulate Ca2+ concentrations in body fluids. Its net effect upon release is to reduce the concentration in body fluids by inhibiting osteoclasts (thus reducing Ca2+ release from bones) and by stimulating Ca2+ excretion in the kidneys. Calitonin release is stimulated by a rise in Ca2+ concentration in the blood. Embyrology Around 3-4wks gestation, the thyroid appears as an proliferation of the epithelium at the base of the tongue, at a point that will eventually become the foramen caecum. It then descends in front of the pharyngeal gut as a bilobed, hollow, fluid-filled structure by travelling through the thyroglossal duct. It subsequently moves to the base of the neck, anterior to the hyoid over the following weeks. Throughout the whole process, the tongue remains connected to the thyroid via the thyroglossal duct. Thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone start being secreted from the hypothalamus and pituitary gland around 18-20wks gestation, and fetal thyroxine (T4) release reaches a clinically significant level at around the same time. Fetal triiodothyronine (T3) remains low until 30wks. This fetal self-sufficiency is a safeguard against abnormal brain development that can be caused by maternal hypothyroidism. C cells are originally derived from the neural crest, first seen as the ultimobranchial body, which itself is formed from the ventral portion of the fourth pharyngeal pouch. Thyroid hormones 'T3 and T4' The hormones that have an effect on thyroid function are TRH and TSH. The thyroid itself releases T3, T4, and calcitonin. T3 and T4 are tyrosine-based hormones who are primarily involved in metabolism regulation. The other essential ingredient is iodine absorbed from food. T3 contains 3 iodine atoms, and T4 contains 4, but they are otherwise identical. Iodine deficiency from malnutrition or malabsorption causes a decrease in T3 and T4 production, leading to an enlarged thyroid (goitre). A deiodinase deficiency will also mimic goitre symptoms. T4 is much more abundant in the blood than T3 (by a ratio of 20:1) and has a much longer half-life. T4 is largely biologically inactive, and is converted to the active T3 in cells by deidoinases. T3 is further processed by decarboxylation and deiodination to form iodothyronamine (T1a) and thryonamine (T0a). Deiodinases all contain selenium, hence dietary selenium is also essential for T3 production. 'Synthesis' # Thyroglobulin is released from the RER in follicle cells and is exocytosed to enter the follicle colloid. #Iodide ions are absorbed from food in the GI tract and delivered to the thyroid gland by the bloodstream. Na+/I- symporters in the basement membranes of follicular cells actively transport the I- ions into the cell. Normally, the follicle cells' intracellular iodide concentrations are many times higher than in the blood or extracellular fluid. #The iodide ions diffuse to the apical surface of the cell and passively exits the cell via the transporter pendrin. #In the colloid, thyroid peroxidase converts the ions anactivated form of iodide (I0 or I3-) through oxidation, in a process called organification. #The oxidised iodide is incredibly reactive, and attaches itself to tyrosyl residues on the thyroglobulin molecue. Thyroglobulin has around 120 of these binding points on its 70 tyrosine components. This process forms either monoiodotyrosine (MIT) when 1 iodide ion joins or diiodotyrosine (DIT) when 2 iodide ions join. The process is hastened by iodinases. #The molecule undergoes conjugation and adjacent tyrosyl residues are paired up. T3 is formed when an MIT moiety bonds to a DIT moiety. T4 is formed when two DIT moieties bond. #The iodinated thyroglobulin binds to megalin receptors on the apical membranes of the follicle cells. Endocytosis here is stimulated by the actions of TSH. #Lysosome containing various proteases fuse with the endocytosed molecules and cleave T3 and T4 molecules from them. Not all of a thyroglobulin molecule becomes thyroid hormone. Around 75% of it remains as DIT or MIT and their iodine ions are recycled by deiodinases. #The vesicles containing T3 and T4 then fuse with the basal membrane and exocytose their contents into the bloodstream. Depending on the body's current needs however, they may also be stored in the follicles awaiting transport. The follicles store unnecessary thyroid hormone until it is needed. The thyroid is unusual compared to other endocrine glands in that it is capable of storing vast amounts hormones for use later. The stores in the thyroid are able to supply the body's normal requirements for 2 to 3 months, therefore when there is a problem with thyroid hormone production, its effects will not be observable until 2-3 months later. 'Transport' Upon entry into the bloodstream, over 99% of the T3 and T4 immediately binds to several plasma proteins synthesised by the liver. They mainly bind to thyroxine-binding globulin, and to a lesser extent, to thyroxine-binding prealbumin and albumin. Their high affinity for the binding proteins mean that they are released very slowly to cells. T4 binds more strongly than T3. Half of the thyroxine (T4) in the blood is released into tissue cells roughly every 6 days, whereas half the triiodothyronine - with a shorter half-life - is released every day or so. Upon entering target cells, they again bind to intracellular proteins (again, T4 binds more strongly), and exert their effects slowly over a period of days to weeks. 'Functions' T3 and T4 are wide reaching hormones that have an effect on almost every cell in the body. They enter target cells via an energy-dependent transport system. Once inside the cell, they bind to receptors in the cytoplasm, in the nucleus, and on the surface of mitochondria. *Those bound to cytoplasmic receptors are essentially held in storage for when they're needed. If intracellular thyronine concentration falls, then the cytoplasmic receptors release their bound hormone. *The thyronines that bind to mitochondria increase the rate of ATP production *Those that bind to receptors in the nucleus activate genes that control the synthesis of enzymes involved in energy transformation and utilisation. For example, thyronine binding can result in an increase in production of Na+/K+ ATPase, the membrane protein responsible for the ejection of sodium and recovery of potassium. Furthermore, thyroid hormones also activate genes that code for the synthesis of enzymes involved in glycolysis and ATP production. This, combined with the effects of thyroid hormones on mitochondria serve to increase a cell's metabolic rate. The increase in energy use also causes an increase in heat generation, a consequence called the calorigenic effect of thyroid hormones. In young children, TSH production increases during cold weather, and the calorigenic effect may allow them to adapt to colder climates. Nuclear receptors for thyroid hormone are either attached to the DNA themselves or are in close proximity to them. The receptors normally form heterodimers with retinoid x receptors (RXR) at specific thyroid hormone response elements on DNA. When thyroid hormones bind to them, transcription is initiated. Large numbers of several different types of mRNA are formed and translated over the subsequent minutes to hours. Not all protein production is increased equally however, and most of the effects of these hormones are believed to be a result of enzymatic activity and other functions of these newly produced proteins. Essentially, T4 (and to a lesser extent T3), travels in the bloodstream bound to proteins until they enter a cell via ATP-dependent carrier proteins. After conversion to T3, they are either stored, increase ATP production by binding mitochondria, or travel to the nucleus where they increase the production of several proteins by binding to a heterodimer of DNA strands and retinoid X receptors. These proteins, created under the influence of increased thyroid hormone, have several effects, including: *Stimulation of growth *CNS development *Cardiovascular effects - increased cardiac output, heart rate, heart strength, and blood flow *Increased respiratory volume and rate *Metabolic effects - increased number and activity of mitochondria, activity of Na+/K+ ATPase, O2 consumption, glucose absorption, gluconeogenesis, glycogenolysis, lipolysis, protein synthesis, and basal metabolic rate (BMR) *Causes cells to leak sodium, activating the Na+/K+ pumps more *Increases the body's requirements for vitamins and nutrients *Decreased serum cholesterol (by increasinng LPL receptors on liver cells, more LPL is removed from the blood, and the attached cholesterol is secreted in bile and excreted in faeces), phospholipids, and triglycerides, even though there is increased free fatty acids *Decreased body weight and increased appetite (although these two may offset each other) *Persisting tiredness but difficulty sleeping due to excitatory effects on CNS *Increases in secretion of almost all other glands (e.g. an increase in glycolysis stimulation requires an increase in insulin release) *Normal sexual function requires normal levels of thyroid hormones. Lack of thyronines can cause loss of libido and abnormal or absent periods. Excess can cause impotence or oligomenorrhoea (exceedingly light periods). As a result of all of these it also increases heat production, observable in those with thyroid dysfunction who are often poor at regulating body temperature. Thyroid hormones are especially essential in growing children. Hypothyroidism at a young age causes severe growth and develpomental retardation, whereas hyperthyroidism will cause excessive skeletal growth at a young age, but will also cause early closing of the epiphyses and full height may actually be reduced. 'Regulation of secretion' Regulatory mechanisms operate through the actions of the hormones TRH and TSH. 'TSH' TSH (thyroid stimulating hormone, or thyrotropin), is a hormone secreted by the anterior pituitary gland, whose release is regulated by TRH from the hypothalamus. It is a glycoprotein that acts on the thyroid to induce increased secretion of T3 and T4. It does this via several routes: *Increased proteolysis of the thyroglobulin stored in the follicles *Increased activity of the Na+/I- symporter, so more iodide is 'trapped' in the epithelial cells *Increased iodination of tyrosine, resulting in more thyronine formation *Increased size and secretory activity of the thyroid cells *Increased number of thyroid cells, a change from cuboidal to columnar epithelium, and more infolding of thyroid cells into the follicles. TSH administration or release will initiate proteolysis of thyroglobulin and subsequent thyronine release into the bloodstream within 30 minutes. However, the effects of the hormones will take anything from hours to weeks to develop. Cyclic adenosine monophosphate (cAMP) mediates the stimulatory effects of TSH. Once TSH binds to specific TSH receptors on the surface of thyroid epithelial cells, adenylyl cyclase in the membrane is activated, increasing cAMP formation. cAMP then acts as a second messenger by activating protein kinase, causing phosphorylations throughout the cell. This results in an immediate increase in secretion of thyronines and prolonged growth of thryoid glandular tissue. 'TRH' TRH (thryotropin-releasing hormone) is hypothalamic hormone responsible for regulating TSH release, secreted by nerve endings in the median eminence of the hypothalamus. It travels to the anterior pituitary gland via the hypothalamic-hypophysial portal blood. Blockage of the portal will greatly decrease TSH secretion, but will not reduce it to zero. Upon binding to specific TRH receptors, it activates the phospholipase C second messenger system, which is followed by a cascade of other second messengers, including Ca2+ ions and diacyl glycerol (DAG), resulting ultimately in TSH release. 'Importance of dietary iodine' Iodine from food is a component of thyroid hormones, and thus is essential to proper thyroid function. Seaweed or kelp are the most reliable foods for iodine content, but seafood, eggs and dairy, and other animal products are generally good sources. They are actively transported into the bloodstream from the gut as I- ions. Minimum daily values for proper functioning are 120-150µg, although supplementation of salt in most developed countries means that daily intake is usually around 500µg. The liver excretes around 20µg daily in bile (regardless of iodine intake), whilst much of the unnecessary iodine is excreted in the urine.